α1-Antitrypsin (AAT) or α1-protease inhibitor (α1PI) is a natural inhibitor of proteases released by activated neutrophils. AAT is a glycoprotein consisting of 394 amino acids and having a molecular weight of 52 kD. Human AAT is expressed as a 418-amino acid precursor from which a 24-amino acid precursor is clipped to yield the 394-amino acid final product. AAT is synthesized primarily in the liver, but expression has also been demonstrated in neutrophils, monocytes and macrophages.
Low or zero plasma levels of AAT constitute a risk factor for the development of emphysema due to the unopposed and destructive action of neutrophil proteases in the lungs. For the prevention and/or treatment of AAT deficiency-related emphysema, AAT augmentation therapy has been developed (Mulgrew et al., 2007).
Currently, patients with AAT-deficiency-associated emphysema are treated with a high dose of plasma-derived (pd)AAT (60 mg/kg/week; PROLASTIN® from Talecris, ARALAST® from Baxter and ZEMAIRA® from ZLB). Large quantities and frequent injections of AAT are required to relieve AAT-deficiency-related emphysema. A major concern with the plasma-derived material is the safety of the preparations. As with all human-derived material, potential risk of pdAAT is contamination with prions or other adventitious agents. A second concern is the limited availability of the plasma material.
Human plasma-derived AAT contains three N-linked glycans at Asn residues 46, 83 and 247. These glycans consist of mostly di- and tri-antennary structures. A high degree of sialylation of the glycans on recombinant proteins is of importance for optimal pharmacokinetics (PK).
Until now, recombinant production of AAT has been hampered by low expression in most recombinant platforms (Karnaukhova et al., 2006). Recombinant AAT has been produced at high levels in transgenic systems, but clinical development thereof has been stopped because of suboptimal pharmacokinetics (PK) and safety issues due to non-human contaminants (Spencer et al., 2005).